Much of the effort in the immunotherapy of human cancer has focused on malignant melanoma. This is attributable to clinical observations suggesting that cutaneous melanomas are antigenic and to experimental studies demonstrating anti-melanoma immune responses in patients. In spite of the fact that melanomas may be among the most antigenic of human cancers, attempts to control this disease using immunological approaches have been disappointing because of an inability to completely eradicate melanoma metastases. We have developed a syngeneic murine model with which to investigate the reasons for the failure of immune mechanisms to control melanoma metastases. In this model, the growth and resection of local K1735-M2 melanoma tumors in syngeneic hosts leads to the development of a high level of systemic immunity, as indicated by the ability of the mice to reject subcutaneous challenge with melanoma cells. Nonetheless, many of these animals subsequently die from pulmonary metastases derived from the original immunizing inoculum. The objectives of the proposed studies are (a) to investigate, in a systematic way, the reasons for the failure of immune effector mechanisms to control pulmonary melanoma metastases and (b) to develop approaches for inducing effective T-cell-mediated immunity in the lungs. For part (a) we will test three specific hypotheses: 1) Melanoma metastases have undergone immunoselection in vivo and are no longer recognized by immune effector cells. 2) Immune effector cells that reach the lungs fail to function in the pulmonary microenvironment, because if inhibitory substances produced by the lungs or by the melanoma metastases. 3) Immune effector cells induced by s.c. immunization fail to home to the lungs. For part (b), we will use a T- cell receptor transgenic mouse model to determine how to induce mucosal immunity that will provide an effective T-cell-mediated immune response in the pulmonary compartment. We will then test the hypothesis that induction of mucosal immunity provides better protection against pulmonary metastases than conventional s.c. immunization. These studies should provide insights as to why melanoma metastases escape from immunological control and may suggest new approaches for more effective immunotherapy of pulmonary metastases.